Despite the obvious clinical effects that alcohol has on the brain, there is little information on the neuropathology of excessive long-term use of alcohol without other complicating medical conditions. We and others have already documented cerebral and cerebellar cortical changes but there is good evidence to suggest that subcortical pathology also plays an important role in this disorder. The aim of the present proposal is to serially section specific subcortical brain regions from chronic alcoholics without additional medical problems in order to locate and quantify subcortical alcohol-specific neuropathology. In particular the size, morphology, number, location and neurotransmitter content of neurons in brainstem, diencephalon and basal forebrain regions will be analyzed. The justification for the choice of these regions is dealt with in sections B6 and C2.4. The brain sections will be stained using immunohistochemical and classical neuropathological techniques and analyzed using computer-assisted morphometry. Serial sections will be combined to give three dimensional images of the number and distribution of neurons in these nuclei. The findings will be compared with carefully selected control (normal) cases and will be correlated with ongoing studies on alcoholic patients with specific neurological disorders such as the Wernicke-Korsakoff syndrome (WKS) . This type of comprehensive analysis has not yet been attempted and few studies have addressed the possibility that alcohol itself may cause brain damage and hence explain clinical and cognitive deficits. Specific questions to be addressed include: Do only certain neuron types within particular brain regions degenerate and what is the pattern of degeneration? Are specific anatomical pathways or neuronal populations with a similar chemistry affected? Is there a similar pathological profile for all alcoholics? How does this profile differ with regard to the patient's age, quantity and duration of alcohol intake, or associated neurological disorders such as the WKS.